Process of making polymeric hydrogels by reactive extrusion

ABSTRACT

What is described is a reactive extrusion process of making a polymeric hydrogel of a polymeric anhydride or acid, e.g. maleic anhydride or maleic acid polymer, or copolymer thereof, crosslinked with a crosslinking agent containing at least 2 crosslinkable groups, particularly, —OH or —NH 2 , or both. The reaction product is a crosslinked polymeric ester or amide/imide, or both, suitably having a mole ratio of —OH, or —NH 2 , to —COOH, of 1:10 to 10:1, preferably 2:10 to 7:1. The hydrogel is particularly swellable in water, e.g. &gt;100% in 1 hour in aqueous media; and forms a thin, tacky layer on a substrate, which property is useful in bioadhesive products.

CROSS REFERENCE TO RELATED PATENTS AND APPLICATIONS

This patent application is a continuation-in-part of pending U.S. patentapplication Ser. No. 10/397,900, which is a division of U.S. patentapplication Ser. No. 10/177,995, now U.S. Pat. No. 6,583,225.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to hydrogels, and, more particularly, topolymeric hydrogels which are crosslinked polymeric esters oramides/imides, or both, of a polymeric anhydride or acid, or copolymersthereof, which are very swellable in water, and form thin, tacky layerson a substrate, and bioadhesive products thereof.

2. Description of the Prior Art

Hydrogels are polymeric materials which can swell appreciably in water.However, what is described as hydrogels can be viscous polymericsolutions without the swelling characteristic of a true hydrogel. Suchhydrogels also are not tacky, a necessary property for makingbioadhesive products. See U.S. Pat. Nos. 4,740,365; 4,990,551;5,135,753; 5,336,501; and 5,846,214. Accordingly, it is desired toprovide new and useful polymeric hydrogels having exceptional swellingproperties in water, and which are tacky; and bioadhesive products ofsuch hydrogels.

SUMMARY OF THE INVENTION

What is described herein is a reactive extrusion process of making apolymeric hydrogel which is a polymeric anhydride or acid or copolymerthereof, e.g. maleic anhydride or maleic acid polymer, or copolymerthereof, preferably with an alkylvinylether; e.g. methylvinylether orisobutylvinylether; or an olefin, e.g. ethylene, butylenes orisobutylene; crosslinked with a crosslinking agent having at least 2crosslinkable groups; e.g. an alcohol, —OH, an amine, —NH₂, oralcohol-amine groups, e.g. polyols such as polyvinyl alcohol, glycerol,glucose, sorbitol, pentaerithyritol, nonionic surfactants, alginates,starch, cellulose and its derivatives, ethylene glycol, diethyleneglycol and ethoxylated/propoxylated derivatives thereof; or a polyamineor ethoxylated amine, e.g. an aminoalcohol, amino acid and the like.

The polymeric hydrogel of the invention preferably has a mole ratio of—OH or —NH₂:COOH of 1:10 to 10:1, most preferably 2:10 to 7:1.

The polymeric hydrogel herein is particularly characterized by itsexceptional swelling properties and tackiness, which are useful formaking bioadhesive products.

The polymeric hydrogels of the invention are made by reacting a maleicanhydride or maleic acid polymer, or copolymer, with a crosslinkingagent having at least 2 crosslinkable groups, particularly a polyol orpolyamine, or alcohol amine, in water as solvent, in the presence of anesterification or amidation catalyst.

The reaction product is a crosslinked polymeric ester or amide/imide, orboth.

Generally the polymer hydrogels of the invention contain a considerableamount of water, usually about 20 wt % or more.

DETAILED DESCRIPTION OF THE INVENTION

The polymeric hydrogel of the invention is made by a crosslinkingreaction between an acidic polymer, particularly copolymers of maleicanhydride or maleic acid, or mixtures thereof, and a comonomer, e.g. analkylvinylether, such as methylvinylether or isobutylvinylether, orolefin, e.g. ethylene, butylenes or isobutylene; with a suitablecrosslinking agent, i.e. a compound having at least 2 groupscrosslinkable with such copolymers, such as present in polyols, diols,triols, etc. present in compounds such as glycerol, pentaerithyritol,sorbitol, and nonionic surfactants;, in polymers such as polyvinylalcohol (PVOH), sugars, e.g. glucose, saccarose, alginates, starch,cellulose, and its derivatives; or amines, or aminoalcohols, present andin polyamines, polyaminoalcohols, ethoxylated amines, amino acids, e.g.arginine, glutamine, lysine and gelatine.

The crosslinking reaction produces a crosslinked polymeric ester oramide/imide, or mixed ester-amide/imide. Unexpectedly this reactionsuitably is carried out in an aqueous solution or slurry of polymer andcrosslinking agent in the presence of an esterification or amidizationcatalyst, e.g. sulfuric acid, phosphoric acid or toluene sulfonic acid,at about 60-150° C., preferably 80-140° C.

Preferably the hydrogel is formed by a reactive extrusion process.

The polymeric hydrogel obtained has advantageous swelling properties invarious solvent media e.g. water, base, salt, buffers, etc. When appliedto a substrate, the polymeric hydrogel of the invention forms a thin,tacky layer suitable for use as a bioadhesive. The hydrogels also areuseful in oral care, personal care, wound care and drug deliverysystems.

The physical properties of the hydrogel, e.g.swelling/tack/solubility/rate of drying/dispersibility in water, andviscoelastic properties, and feel, etc. can be predetermined by the moleratio of —OH or —NH₂:COOH in the hydrogel, as well as the reactionconditions employed, e.g. temperature, catalyst, reaction time, amountof water, etc.

Preferably the mole ratio of —OH or —NH₂:COOH in the hydrogel is 1:10 to10:1, most preferably 2:10 to 7:1.

The process of the invention is carried out in an extruder having afirst section in which the reactants are blended and a second sectionwhich can be heated to a selected reaction temperature. A suitableextruder for use in the process of the invention is the Wemer &Pfleiderer twin screw extruder, e.g. ZSK-30, however other extruderswhich meet the process requirements of the invention also can be used.The process can be advantageously modified by connecting two extrudersin series.

The bioadhesive hydrogels of the invention find wide application in manyproducts, such as topical drug and cosmetic delivery systems; e.g. skinand mucous membranes; personal care products such as skin care; an oralcare, e.g. denture liners, flavor and drug delivery; wound care and insystems for drug delivery.

EXAMPLE 1

Into a 14 barrel ZSK-30 twin screw extruder (Wemer & Pfleiderer) thereare fed two reagents' streams: aqueous solution of 20 % wt. poly(vinylalcohol) (PVOH), containing 20 g/l p-toluenesulfonic acid catalyst andGantrez® AN 169 BF (methyl vinyl ether/maleic anhydride copolymer, madeby ISP) powder. The rate of feeding Gantrez AN 169 BF is such that theweight ratio of PVA/Gantrez is maintained at the desired level, e.g.about 2 in most runs. The components are mixed intimately in the firstbarrel, which is maintained at 60° to 90° C. The next zone (reactionzone) consists of barrels 2-14, where the temperature is kept at 110° to150° C. If, however, partial devolatilization of water is desired, thereaction zone consists of barrels 2-9 only, and barrels 10-14 are usedfor partial evaporation of water and removing trace amount of residualsolvent. The devolatilization zone is kept under vacuum at 60° to 100°C. Throughput rates are 10 to 20 lbs/hr.

The material is continuously extruded, through the die, at the surfaceof moving belt covered with non-woven polyester sheet. Thin tacky layerof semi- transparent, strong, slightly rubbery hydrogel on substrate isobtained. The hydrogel on polyester substrate can be cut into desiredshape and can be used for wound care, skin care, drug delivery andsimilar applications. Other substrates can be used in the process andother continuous shapes can be extruded as well.

Characteristics of the material can be adjusted by varying thefollowing:

-   Feeding of PVOH solution and Gantrez powder: faster feeding—softer    and more tacky material-   PVOH/Gantrez ratio: more PVOH—more rubbery, less tacky material-   Devolatilization in the final zone: material having less water, i.e.    more rubbery, less tacky-   Higher temperature in the reaction zone: more rubbery, less tacky    material-   PVOH/Gantrez ratio increasing, % swelling in water decreases

EXAMPLE 2

Using the extruder and parameters as in Example 1 the hydrogel is madeby feeding into first barrel aqueous solution containing 100 g/l methylvinyl ether/maleic acid copolymer (Gantrez® S 97 made by ISP as 12 to 14wt. % aqueous solution), 250 g/l glycerol and 12.5 g/l sulfuric acid.The product was extruded as above. The material is a transparent, soft,flexible, tacky hydrogel. It is softer and more tacky, and its' degreeof swelling in water is higher than that of the material obtained inExample 1. Its properties can be adjusted in a way similar to Example 1.

EXAMPLE 3

Using the extruder and parameters as in Example 2 the hydrogel is madeby feeding into first barrel aqueous solution containing 100 g/l methylvinyl ether/maleic acid copolymer (Gantrez® S 97), 68 g/l sorbitol and12.5 g/l sulfuric acid. The product is extruded as above. Its feel andother characteristics are similar to material made according to Example2. Its properties can be controlled by adjusting reaction parameters asin Example 1.

While the invention has been described with particular reference tocertain embodiments thereof, it will be understood that changes andmodifications may be made which are within the skill of the art.

1. A process of making a polymeric hydrogel comprising maleic anhydrideor maleic acid polymer, or copolymer thereof, with an alkylvinylether orolefin, crosslinked with a crosslinking agent having at least 2crosslinkable groups, where the crosslinkable group is selected from thegroup consisting of an alcohol (—OH), amine (—NH₂) or alcohol-amine(—OH) (—NH₂), and water which comprises forming a reaction mixture ofmaleic anhydride or maleic acid-polymer or copolymer thereof with analkyl vinyl ether or olefin, with said crosslinking agent, in apredetermined portion as a paste or slurry with water, and reacting andextruding the paste or slurry at a predetermined temperature to formsaid polymeric hydrogel.
 2. A process according to claim 1 wherein saidcrosslinking agent is a polyol.
 3. A process according to claim 2wherein said polyol is selected from the group consisting of polyvinylalcohol, glycerol, glucose, sorbitol, pentaerithyritol, nonionicsurfactants, alginates, starch, cellulose.
 4. A process according toclaim 1 wherein said crosslinking agent is a polyamine or ethoxylatedamine.
 5. A process according to claim 1 wherein said crosslinking agentis an aminoalcohol.
 6. A process according to claim 4 wherein saidpolyamine is an amino acid.
 7. A process according to claim 1 whereinthe mole ratio of said alcohol (—OH) or amine (—NH₂) groups in thecrosslinking agent to carboxyl groups (—COOH) in the polymer orcopolymer is 1:10 to 10:1.
 8. A process according to claim 7 whereinsaid mole ratio of —OH or —NH₂:COOH is 2:10 to 7:1.
 9. A processaccording to claim 1 wherein water is present in an amount of at least20% by weight of the hydrogel.
 10. A process according to claim 1 inwhich the crosslinked polymer is an ester or amide/imide, or both.